Every year thousands of babies are born with genetic diseases. Often, the parents of these children are both healthy, but each parent possesses genetic mutations that when passed in combination to the child, endow it from the time of conception with an unmitigated genetic defect. Children with such diseases may suffer, have diminished lifespans and can entail large emotional and financial costs, so many prospective parents attempt to minimize the chance that they pass on genetic elements that cause disease.
Carrier testing, in which both parents are genotyped at loci of their genomes that are known to cause disease, is a technique widely used to achieve this goal. Such tests rely on a defined set of alleles known to cause diseases, and then screen for the presence of these alleles in one or both parents prior to conception. The alleles screened in such tests typically have been established to cause disease by examining pedigrees of patients with the disease, by using cellular or animal models of the effect of the particular allele, or alternate means. In all cases, the correlation between alleles and genetic diseases are determined by studying one or more individuals that have already been born.
Although carrier testing is used in a limited number of cases, even if all possible prospective matings were filtered by this technique, children suffering from genetic diseases would still be born. This is because carrier tests inherently screen only a known subset of all alleles that can cause disease. The incompleteness of these tests is evidenced by the fact that the number of alleles associated with disease in public databases such as ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) and OMIM (http://www.ncbi.nlm.nih.gov/omim) continues to grow every year, and in turn so do the number of loci tested by carrier screening. Similarly, many patients can present with pathologies which appear to have a genetic basis, but for which no specific underlying genetic mutation has yet been determined. In many of these cases, a novel pathogenic variant or variants is then later discovered by various means and added to the catalog of known disease associated mutations. For example, the genomes of many patients with similar pathologies can be sequenced and shared mutations found. Alternatively, mutations that occur in an individual patient's genome which appear damaging (missense, nonsense, etc.) and are present in genes known to be associated with a biological process related to the pathology, may be tested in a cellular or animal model.
While the steady increase of the catalog of variants known to cause disease implies that carrier testing will get better, it also evinces that it suffers from two fundamental inadequacies. The first is that a diseased child must be born and diagnosed in order to find a new disease associated allele. The second, and more insidious, is that carrier testing cannot assess the impact of novel or de novo mutations. If a variant is specific to an individual or family and has not been previously studied, carrier testing cannot determine what effect it may have on future offspring. Additionally, because novel variants initially only appear as one half of a heterozygote genotype, if the allele is recessive, but damaging when combined with itself or another recessive mutation, it is very difficult to resolve the effect of the mutation until, from the perspective of a parent who wants to avoid passing on disease causing alleles, it is too late.